Carbon–carbon bond activation of cyclobutenones enabled by the addition of chiral organocatalyst to ketone

ARTICLE Received 21 Oct 2014 | Accepted 5 Jan 2015 | Published 5 Feb 2015 DOI: 10.1038/ncomms7207 OPEN Carbon–carbon bond activation of cyclobutenones enabled by the addition of chiral organocatalyst to ketone Bao-Sheng Li1, Yuhuang Wang1, Zhichao Jin1, Pengcheng Zheng2, Rakesh Ganguly1 & Yonggui Robin Chi1,2 The activation of carbon–carbon (C–C) bonds is an effective strategy in building functional molecules. The C–C bond activation is typically accomplished via metal catalysis, with which high levels of enantioselectivity are difficult to achieve due to high reactivity of metal catalysts and the metal-bound intermediates. It remains largely unexplored to use organocatalysis for C–C bond activation. Here we describe an organocatalytic activation of C–C bonds through the addition of an NHC to a ketone moiety that initiates a C–C single bond cleavage as a key step to generate an NHC-bound intermediate for chemo- and stereo-selective reactions. This reaction constitutes an asymmetric functionalization of cyclobutenones using organocatalysts via a C–C bond activation process. Structurally diverse and multicyclic compounds could be obtained with high optical purities via an atom and redox economic process. 1 Nanyang Technological University, Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Singapore, 637371, Singapore. 2 Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China. Correspondence and requests for materials should be addressed to Y.R.C. (email: ). NATURE COMMUNICATIONS | 6:6207 | DOI: 10.1038/ncomms7207 | www.nature.com/naturecommunications & 2015 Macmillan Publishers Limited. All rights reserved. 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms7207 T he catalytic activation of a carbon–carbon (C–C) single bond of cyclobutenones can provide direct methods towards building useful molecules1–5. Despite the rather clear practical significance, C–C bond activation remains challenging. Traditionally, this process is initiated by the oxidative addition of a transition metal catalyst to the C–C bond followed by other bond breaking and formation events (Fig. 1a). Due to the high reactivities of the metal catalyst and the metal-bound intermediates, chemoselectivity is generally difficult to control. In addition, it still remains difficult to achieve high levels of enantioselectivity using the transition metal-catalysed C–C bond activation approach6–11. In many cases, intramolecular reactions were used to overcome the challenging selectivity issues. Our laboratory is interested in developing organocatalysis for challenging bond activations while maintaining the power of organocatalysis for chemo- and stereo-selectivity control. Herein, we report the addition of an N-heterocyclic carbene (NHC) organocatalyst to a ketone moiety that initiates a C–C single bond cleavage to generate an NHC-bound intermediate for chemo- and stereo-selective reactions (Fig. 1b). Compared with the earlier NHC catalysis (such as oxidative NHC catalysis for g-carbon functionalization of enals)12–18, in this approach all atoms of the substrate end up in the product (atom economy) and the overall reaction is redox-neutral (redox economy)19. Specifically, the addition of an NHC catalyst to an unsaturated four-membered cyclo-ketone substrate to form intermediate I. Breaking a C–C bond of the four-membered ring eventually generates a vinyl enolate intermediate12–22 II that reacts with an imine substrate to form the lactam product. NHC catalysis is routinely used in the activation of aldehydes through the formation of Breslow intermediates23–32. The addition of NHC catalyst to ketone moiety for reactions is much less studied, except for the activation of a-hydroxyl ketones via retro-benzoin pathways as nicely illustrated by Bode and co-workers33,34. Our interest in aza-quaternary center compounds35 with important biological activity motivated us to use fourmembered cyclo-ketone substrate (1a) and imine (2a) as model substrates for the search of suitable catalytic conditions (Table 1). As an important note, although four-membered cyclo-ketones were nearly untouched in organocatalysis, this class of molecules caught considerable attentions in the field of transition metal catalysis (Fig. 1a). Murakami et al.36,37 have pioneered the nonenantioselective C–C bond activation of four-membered cyclic ketones to react with olefins in an intramolecular fashion38–42. Recently, impressive enantioselective intramolecular reactions enabled by the metal-catalysed C–C bond activation of fourmembered cyclo-ketones were reported by the groups of Dong10 and Cramer11. The related cyclobutanol has also been used in the synthesis via C–C bond breaking to build sophisticated molecules, as illustrated by Trost,43 Tu44,45 and others43–47. Results Reaction optimization. As briefed in Table 1, triazolium NHCs (A, B, entries 1 and 2) could smoothly mediate the formation of desired product 3a as essentially a single diastereomer. The N-aryl substituent (phenyl or mesityl) of pre-catalyst A48 and B49,50 had little effect on the reaction yield. Next the enantioselectivity of this transformation was evaluated with aminoindanol-derived triazolium salts C–F49–52 (entries 3–6). In all cases, the product 3a was formed essentially as a single diastereomer with good yields (entries 1–6). Among precatalysts C–F, the N-aryl substituents could affect the reaction enantioselectivities (entries 3–6). The use of N-mesityl substituted triazolium catalyst D48 gave the product 3a with the highest enantioselectivity (90:10 er) and good yield (84%, entry 4). We then noticed that increasing the reaction temperature to 55 °C could reduce the reaction time from 48 to 24 h and there was a small but reproducible increase of Table 1 | Condition optimization. a Metal-catalysis carbon-carbon activation (literature) O O [M] (metal cat.) Oxidative R addition O Migratory insertion a M O M b Reduction a elimination a b b R R R (typical approach for metal-catalyzed activation C-C bond) b Organocatalytic carbene C-C bond activation (this work) O O N NR3 + R R′ R1 (±) 1 N R2 NHC catalysi s N NR3 R2 R C-C bond activation 2 R1 R′ ♦Atom economy ♦Redox economy 3 NHC NHC N N O O O N N 2 N N R I R′ N NR3 formal [4+2] R2 R R R′ II N N III R1 R′ Figure 1 | NHC-catalysed cyclization via carbon–carbon bond activation of ketones. (a) Metal-catalysed activation of carbon–carbon bond. (b) Our synthetic proposal via an organocatalysis. NHCs react with cyclobutenone to generate chiral vinylenolate intermediate to give novel formal cycloaddition reactions. 2 Entry 1 2 3 4 5 6 7 NHC A B C D E F D, 55 °C, 24 h 3a yield (%)w 71 75 81 84 83 55 83 3a er (%)z — — 83:17 90:10 64:36 75:25 92:8 NHC, N-heterocyclic car (...truncated)